Our fundamental objective in this Program is to leverage our long-standing, multi-institutional commitment to studying chronic lung disease, including interstitial lung diseases, to develop new insights into the genetics and pathogenesis of Idiopathic Pulmonary Fibrosis (IPF) and the familial form of this syndrome known as Familial Interstitial Pneumonia (FIP). Currently, we have enrolled >1200 families with FIP and hundreds of patients with IPF into our disease registry, thus facilitating discovery of a number of disease-associated genes and pathways which have helped to shape our current understanding of the underlying mechanisms that lead to progressive lung fibrosis. Despite substantial progress during the first phase of funding for this Program, there is far more work to be done to unravel the complex genetic architecture of interstitial lung disease. Our Program is fortunate to join together a talented and experienced team of collaborative investigators, supportive institutions with robust infrastructure, and a large number of patients and families who are highly motivated to support research into this area. Based on these assets, we believe that over the next funding period we have a unique opportunity to re-shape understanding of interstitial lung disease by identifying new disease- associated genes, determining their roles in initiation and progression of disease, and putting these genetic risk factors into the context of environmental, epigenetic, and transcriptomic signals that determine clinical disease manifestations. This work will leverage advances in technology, which continue to rapidly evolve, in order to maximize progress. Our long-term goal is for this knowledge to lead to risk stratification, primary prevention, and effective new therapies for interstitial lung diseae. Project 1 will investigate expression and function of candidate rare genetic variants identified in FIP families. Newly discovered FIP-associated genes will inform our ongoing cohort study of asymptomatic individuals at-risk for FIP that is designed to better define the natural history of FP and characterize genotype-phenotype relationships. Project 2 will utilize whole exome sequencing to identify and prioritize new genetic variants in FIP. In addition, whole genome sequencing of a large cohort of sporadic IPF patients will further investigate the intersection between familial and sporadic pulmonary fibrosis. In addition to genetic analysis, advanced bioinformatics tools will be employed to evaluate and prioritize candidate genes for further study. Project 3 will use a systems biology approach to develop an integrated understanding of how genetic, epigenetic, and transcriptomic signals contribute to the development and severity of IPF. Together, integrated approaches in this Program will lead to new concepts in pathogenesis of FIP and sporadic IPF, and suggest opportunities for novel treatment or prevention strategies.